Chromans and intermediates and process of producing same



' Pate tedjMar. 20, 1945 UNITED STATES PATENT OFFICE OHROMANS AND INTERMEDIATES AND PROCESS OF PRODUCING SAME Lee Irvin Smith, Minneapolis, Minn, and Henry C. Miller, Claymont-Wilmlngton, Del., aasignors to Regents of the University of Minnesota, Minneapolis, Minn., a corporation of Minnesota -No Drawing. Application March 1a, 1942, Serial No. 435,393

10 Claims. (Cl. 280-333),

This invention relates to new methods of pro-- ducing chroman compounds and to new intermediates and methods of producing the same.

The invention relates particularly to the production of 2,2-dialkyl-6-hydroxy substituted chromans, wherein such alkyl substituents may be the same or different, and is of particular significance and usefulness in production of these hydroxychromans wherein the alkyl substituents in the number 2-position differ widely, as for example, in alpha, beta and gamma tocopherols (the tocols).

It is an object of the invention to provide new methods of producing chroman compounds and particularly to methods of producing 2,2-dialkyl- G-hydroxy substituted chromans wherein said alkyl substituents may be the same or different, and to provide new procedural steps and interhalide,.structure I, having the general structure I 0R4 I I Ra MgHa where R1, R2 and Re are hydrogen or alkyl, such as methyl, ethyl, butyl, propyl and the like, R4 is likewise any alkyl such as methyl, ethyl, butyl, propyl or the like, and Ha is chlorine or bromine. For alpha tocopherol R1, R2 and Rs are all methyl, whereas'ior beta or gamma tocopherol, one of them is hydrogen. The 3,6-dialkoxy phenyl magnesium halide may, if desired, be prepared from the corresponding ortho-runsubstituted quinone or ortho unsubstituted hydroquinone-diether, as described in Example A. The 3,6-dialkoxy phenol magnesium halide, structure I, is then reacted with ethylene oxide, and the ethylene oxide product is decomposed with acid and distilled, yielding the primary alcohol structure II, which is a beta hydroxyethyl hydroquinone diether,

II R CH|CH10H where -81, Ra R1 and R4 are as previously defined. This primary alcohol, structure II, is then reacted with a suitable halide compopnd such as thionyl chloride or phosphorous tribromide and is thus converted to the corresponding halide, structure 111:

III CHaCHgHo where R1, R2, R3 and R4 are the same as previously stated and Ha is chlorine or bromine. The

halide then reacted with magnesium to form the corresponding Grignard reagent, structure IV:

IV OHICHIMKHB where R1, Ra, Ra, R4 and He. are as previously defined. The preparation of the Grignard reagent IV is much facilitated by having present with the magnesium a low boiling point alkyl halide, such as ethyl bromide or ethyl chloride,

where R6 and Rs may be the same or diflerent alkyl groups, or one or them may be hydrogen and the other alkyl. Exemplary ketones are acetone (where both R5 and Re are methyl);

methyl ethyl ketone (where R5 is methyl and R0 is ethyl); methyl-n-propyl ketone (where Re is methyl and R6 is n-propyl); methyl-iso-butyl ketone (where R5 is methyl and Re is iso-butyl). An example of the wide variation which may exist between the R5 and Rs'alkyl radicals of the ketone is phytol ketone," (methyl-4,8,12-trimethyl tridecyl ketone) utilized in the preparation of the tocopherol chromans in accordance with the present invention. In this ketone R5 is methyl and R6 is 4,8, -trimethyl tridecyl. The formula oi phytol ketone" is y) H; CH:

Exemplary aldehydes are acetaldehyde (R5 is m bromopseudocumohydroquinone dimethyl ether methyl and Re is hydrogen), propionaldehyde (R5 is ethyl and Re is hydrogen) and the like.

The Grignard reagent, structure IV, and the selected ketone or aldehyde, structure V, are reacted by refluxing and then after acidification, the intermediate tertiary alcohol, structure V1, is obtained:

Rs CHzCH,

I Re R: R

wherein R1 through Rs are as previously defined. The tertiary alcohol structure VI is an intermediate compound and the ether linkages in it may be smoothly de-alkylated (cleaved) and at the same time-the de-alkylated product may be cyclized to the 2,2-dlalky1-6-hydroxy chroman,

by refluxing with acid, in the presence of a solvent for the ingredients. The chroman VII has the structure:

VII

wherein R1, R2, R3, R5, and Rs are as previously defined (the alkyl radical R4 being cleaved and the hydroxyl reintroduced in the de-alkylation). The foregoing procedure is illustrated by the following examples, which, however, must not be considered aslimitations upon the invention claimed. 1

Example A-Preparatitm of 3,6 -dimethozry-2,4,5'- trimethyl phenylmagnesium bromide (structure I) Asolution of grams of bromopseudocumohy droquinone dimethyl ether and 3.0 cc. of ethyl bromide in 40 cc. of absolute ethyl ether was added slowly over a period of minutes to 2.0

grams of magnesium. The mixture was heated under reflux throughout the course of the reaction and resulted in the production of the Grig nard reagent (structure I, R1, R2, R3, and R4 being methyl and Ha being bromine).

Example BPreparatz'on of the primary alcohol compound, beta-hydroaryethyl pseudocumohydroquz'none dimethyl ether (structure II) the Geneva nomenclature.

-of black tarry material.

was removed by steam distillation at atmospheric pressure. The residue was extracted with ethyl ether and the ether then evaporated. The residual yellow oil (5.27 grams) was then dissolved in warm petroleum ether and upon cooling the betahydroxyethyl pseudocumohydroquinone dimethyl ether (structure II when R1, R2, R3 and R4 are methyl) crystallized out. This intermediate primary alcohol may also be designated 3,6- dimethoxy-2,4,5-trimethylbenzyl carbinol, under tallized primary alcohol intermediate was 2.7 grams and had a melting point of 69.5-72C. After several crystallizations from a mixture of ethyl and petroleum ethers, the primary alcohol (II) melted at 73.5-75" C. The yield was better in larger runs than in smaller runs, reaching 29.4 grams (62%) when 55 grams (0.246 mole) of the bromopseudocumohydroqulinone dimethyl ether was used in preparing the Grignard reagent of Example A.

Example C'-Preparation of beta-(3,6-dimethoxy- 2,4,5-trimethylphenyl) ethyl chloride (structure III) Thionyl chloride (14.8 grams) dissolved in dry benzene (10 cc.) was added to a solution of 18 grams of the carbinol intermediate, beta-hydroxyethyl pseudocumohydroquinone dimethyl ether, of Example B, dissolved in 30 cc. of benzene. There was an immediate evolution of gas. The mixture was refluxed for three hours, then cooled and washed successively, twice with Water, once with saturated sodium bicarbonate and again with water. The benzene solvent was then distilled off at atmospheric pressure and a red oil-remained. The red oil was distilled at 3-4 mm. of mercury pressure, leaving 5 to 8 grams The distillate (14.26 grams) was a light yellow oil which boiled at 130-138" C. under 3 to 4 mm. of mercury pressure. The distillate, after crystallization twice from methanol, yielded 8.0 grams of pure white material having a melting point ,of 61.5 C. and 1.1 grams of less pure material, a total of 9.1 grams or 41% yield.

The product, beta-(3,6-dimethoxy-2,4,5-trimethyl phenyl) ethyl chloride has the structure III when the R1, R2, R3 and R4 are methyl and Ha is chlorine.

Example D-Preparatz'on of beta- (3,b-dimethomy 2,4,5-trimethylphenyl) ethyl bromide (structure III) Eight grams of the primary alcohol intermediate, namely beta-hydroxymethyl pseudocumohydroquinone dimethyl ether, of Example B, was dissolved in cc. of petroleum ether havin a boiling point of 3060 C., and the solution was cooled to 0 C. The cooling bath was maintained The yield of crys-' Example Joe-Preparation of 2-ethyl-2,5,7,8-tetraaround the flask containing the primary alcoholpetroleum ether solution, and a solution of 11.4 rams of phosphorous tribromide in 100 cc. of petroleum ether was added slowly over a period of twenty minutes, the solutions being continuously stirred and cooled. The cooling bath was removed and the mixture was allowed to reach room temperature 18 to 20 C.,'and stand for ten hours. The mixture was then refluxed for thirty minutes, after which 40 cc. of water was cautiously-added in small portions. 100 cc. of ethyl ether was then added and the organic layer was washed successively with water, aqueous sodium bicarbonate and again with water, and then dried with sodium sulfate. Removal of the solvent by distillation at atmospheric pressure left 5.5 grams of a yellow oil which was crystallized from methanol. white platelets, which, after several crystallizations melted at 66-67 C.

- The white platelet crystalline product, beta- (3,6-dimethoxy-2,4,5-trimethyl phenyl) ethyl bromide has the Structure III, R1, R2, R3 and R4, in this instance, being methyl and Ha being bromine. 1

Example E--Preparatz'on of 2,2,5,7,8-pentamethyl-6-hydroxychroman (structure VII when R1. R2, R3, R and Rs all are methyl), and esters thereof -(18-21 C.). The thus produced Grignard reagent (structure IV, R1, R2, R3 and R4 being methyl and Ha being bromine) was then reacted with acetone (structure V, R5 and R6 being methyl), 2.00 cc. of acetone being added slowly to the solid Grignard reagent mass. The solid dissolved, and after refluxing fifteen minutes, the mixture was decomposed by addition. of dilute sulfuric acid. The resultant liquid mass separated into aqueous and ether layers. The aqueous layer was separated and extracted with ethyl ether and the ether extraction was combined with the ether layer and the whole dried with magnesium su1- fate. The ethyl ether solvent was then removed by distillation at atmospheric pressure, yielding a residual oil, the intermediate tertiary alcohol (structure VI where all Rs are methyl).

This intermediate carbinol compound was then refluxed for two hours with 10 cc. of acetic acid and 4 cc. of hydrobromic acid, in order to cleave the remaining ether group and cyciize to the hydroxy chroman. The cooled mixture was diluted with Water and the resulting solid removed and purified by crystallizing from methanol. The resulting 2,2,5,7,8-pentamethyl-6-hydroxychroman weighed 0.21 gram and melted at 86.5-94 C. alone or when mixed with an authentic specimen.

This chroman was treated with 3,5 dinitrobenzamide and gave a 3,5-dinitrophenylurethane which ester melted at 203-206 C. alone or when mixed with an authentic specimen.

There resulted 2.8 grams (yield 28%) of methyl-G-hydroxy ,chroman- (structure VII dinitrophenylurethane ester thereof As in Example E, 0.6 gram of magnesium turnings was activated with 1.09 grams of ethyl bromide in 800cc. of ethyl ether and to the thus activated magnesium there was added 2.42 grams of beta -(3,6edimethoxy-2,4,5-trimethylphenyl) ethyl chloride, of Example C. The procedure was carried out as in Example E, to the production of the Grignard' reagent (structure IV, R:, R2, R3 being methyl and Ha being chlorine.) r

The Grignard reagent thus produced was then reacted with 3.0 grams of methylethylketone under the conditions specified in Example 13 except that after decomposition of the Grignard reagent by reaction with the, ketone, all material volatile with steam was removed. The non-volatile portion, i. e., the intermediate carbinol compound (structure VI, where R1, R2, R3 and R5 are methyl and Re ethyl), was demethylated (i. e., cleaved) and cyclized as set forth in Example E, and the resultant crude chroman distilled in a Hickmantype still (bath temperature, -170 C.; pressure 9-10 mm. of mercury pressure). The resultant partially purified chroman was a yellow 01]; yield, 0.63 gram, was rubbed with petroleum ether (B. P. 28-38") and was then crystallized out. After recrystallization from the same solvent, the resultant chroman 2-ethyl-2,5 .'7,8-tetramethyl-G-hydroxy chroman, remained as a white substance having a melting point of 60.5"- 62.5 C.

The 3,5-dinitrophenylurethane was prepared from the chroman of this example and had a melting point of 200201.5 C.

Example G-Z-n-propyl-2,5,7,8 tetramethyl 6 hydrorry chroman (structure VII whereRz, R2,

R3 walks are methyl and R; is n-propyl) The reagents used were 1.21 grams of the intermediate compound, beta- 3.6-dimethoxy-2,4,5 trimethylphenyl) ethyl chloride of Example Cf: 0.55 gram ethyl bromide; 2.0 cc. of ethyl ether:

, lization from petroleum ether, the melting point of the resultant solid chroman was 57 to 59 C. The resulting chroman (structure-VII where R1, R2, R3 and R5 are methyl and R6 is normal propyl) illustrates the diversity of alkyl substituents in the R5 and Rs positions, which may be achieved by the methods of the present invention.

Example H Z-z'so-burl-2,5,7,8-tetramethyl-6- hydroxy chroman (structure VII when R1, R2, R3 and R5 are methyl and R6 is iso-butyl) Example I-Alpha tocopherol (structure VII when R5 is methyl and Re is .f'Fo'r the preparation of this material 0.90 gram (0.038 mole) of magnesium was placed in a. threenecked flask equipped with a stirrer dropping funnel and reflux condenser. A drop of ethyl bromide and a little ethyl ether (0.5 cc.) were added. As soon as the reaction began, the stirrer was started and 4.7 grams (0.0195 mole) of the intermediate compound, beta-(3,6-dimethoxy 2,4,5-trimethylphenyl) ethyl chloride in 10 cc. of ethyl ether was slowly added by way of the dropping. funnel over a period of two hours, during which time the mixture was gently refluxed. Refluxing was continued for four hours after all of the intermediate compound was added, and as a result there was formed a thick precipitate suspension of the Grignard reagent (structure IV when R1, R2, R3 and R4 are methyl and Ha is chlorine).

The thick precipitate suspension of the Grignard reagent was cooled to C. and to it was added 4 grams (0.015 mole) of phytol ketone (structure V where R5 and R6 are as above deflned in this example). The precipitate dissolved, and after refluxing for one hour, the mixture was allowed to cool.

Dilute hydrochloric acid was then carefully added to the cool mixture.- Sometimes, but not always, a small amount (about 0.25 gram) of a solid having an M. P. of ISO-161 C. appears at this point in the process, and is the 1,4-diphenylbutane corresponding to structure III and results from a coupling reaction. After removal of this solid (if any), the mixture was steam distilled and the distillate (750 cc.) was discarded. The residue was thoroughly extracted with ethyl ether and the ether solution was washed with water and dried with magnesium sulfate. The ether was then removed by distillation at atmospheric pressure and left the carbinol intermediate compound (structure VI where R5 is methyl and Re is 4,8,12-trimethyl-tridecyl). The yield was 5.83 grams; 77%.

The carbinol intermediate compound was then demethylated (cleaved) and cyclized by refluxing it for nine hours under an atmosphere of nitrogen and in the presence of '70 cc. of acetic acid containing 6.0 grams of dry hydrogen bromide. Water (2 volumes) was then added and the mixture extracted three times with ethyl ether. The combined ether extracts were washed four times with water, twice with saturated sodium bicarbonate, and once again with water. After drying with magnesium sulfate, the ethyl ether solvent was evaporated.

The residual red oil (5.45 grams) was refluxed for one hour in a nitrogen atmosphere with 50 cc. of ethanol in which 0.5 vgram of sodium had been'dissolved. The solution was diluted with two volumes of water and extracted three times with ether. After washing twice with water, the ether solution was dried with magnesium sulfate and the ether solvent evaporated off. The residual red oil weighed 4.69 grams (yield 72%) and was crude alpha tocopherol.

While the red color of the crude alpha tocopherol could not be entirely removed by shaking with activated alumina (Brockman method) followed by high vacuum distillation, a specimen so treated had a carbon and hydrogen analysis very close to theoretical values for alpha tocopherol. The red color could be removed by boiling the substance in dioxan (10 cc.) with stannous chloride (1.0 gram) and hydrochloric acid (3 cc.), but the product, though yellow and giving good analytical values, was shown by polarographic analysis to be quite impure (52.7%).

A feasible method of purification involves conversion of the crude red oil tocopherol to tocopherolquinone, reducing this to the hydroquinone, and cyclization of the pure tocopherol hydroquinone to alpha tocopherol, according to the method of Tischler and Wendler, J. A. C. S. 60, 700 (1938).

Utilizing this method, the 4.69 grams of crude red oil tocopherol of this example was converted into 1.06 grams (20%) of pure alpha tocopherol, and 2.63 grams of a red oil, probably the partially demethylated carbinol (structure VI) or its dehydration product. This red oil was not investigated further. The 1.06 grams of pure alpha tocopherol was utilized for the following identity tests.

The 3,5-dinitrophenylurethane.--This derivative was prepared in 69% yield, the crude derivative melting at 141.5-155" C. After one recrystallization from ethanol, it melted at 1425-.- 144.5 C., alone or when mixed with an authentic specimen (M. P. 143-145) Polarographic analysis-The buffer in this analysis had a pH of 4.03 and was 0.1 N aniline, 0.1 N anilinium perchlorate in ethanol, 75% by volume. According to this analysis, the purityof the alpha tocopherol prepared in accordance with this invention was 97.2% (limit of experimental error according to this analysis being 3%).

Emmerie and Engel titration.-Duplicate determinations indicate that the sample was alpha tocopherol within the experimental error of the method.

Ultraviolet absorption spectrum-The graph corresponded quite closely to the standard graph for alpha tocopherol, the only difference being a slight disparity in the height of the minimum, a matter of little significance.

Biological assay.--When the alpha tocopherol was fed at a level of 6 mg. to each of eight properly conditioned female rats, there were no resorptions and 100% of good litters averaging 8.4 young each of average weight 5.8 grams were dropped. When fed to each of eight rats at a level of 3 mg. one failed implantation, two resorbed and five littered (71% of '7). The litters averaged seven young each of average weight 5.3 grams. Since the usual specimen of authentic alpha tocopherol shows 50% activity at the 3 mg. level, these results demonstrate that this sample is in every way equal in biological activity to natural alpha tocopherol and to alpha tocopherol synthesized from phytol.

Many obvious variations will be apparent to those skilled in the art and such are intended to be within purview of the invention described and claimed.

What we claim is:

1. The method of making tocopherol-like chr0- man compounds which comprises reacting a Grignard reagent having the structure R CHiCH|MgHa where R1, R2 and Rs are selected from the group consisting oi. hydrogen and alkyl, R4 is alkyl and Ha is selected from the group consisting of bromine and chlorine, with a composition having the structure where one of the radicals in the structure Rs-CO-Rc is alkyl and the other of said radicals is selected from the group consisting of hydrogen and alkyl, and refluxing the resultant tertiary alcoholunder acidic conditions to dealkylate the ether linkages thereof and cyclize to the corresponding G-hydroxy chroman.

2. The method of making chroman compounds which comprises reacting a Grignard reagent having the structure where R1, R2, and R3 are selected from the group consisting of hydrogen or alkyl, R4 is'alkyl and Ha is selected from the group consisting of bromine or chlorine, with an aldehyde having the structure where Re is alkyl, and refluxing the resultant tertiary alcohol under acidic conditions to de-alkylate the ether linkages thereof and cyclize to the corresponding B-hydroxy chroman.

3. The method of making tocopherol-like chroman compounds which comprises reacting a Grlgnard reagent having the structure Ra CBRCHMKH! where R1, R2 and Ra are selected from the group consisting of hydrogen or alkyl, R4 is alkyl and Ha is selected from the group consisting of bromine and chlorine, with a ketone havin the structure Rs-CO-Rs where R5 and Re are selected from the group consisting of like and different alkyl groups and refluxing the resultant tertiary alcohol under acidic conditions to de-alkylate the ether linkages and cyclize to the corresponding 6-hydroxy chroman.

4. The process of making tocopherol-like chromans which comprises reacting beta-(3,6-dialkoxy methylphenyl) ethyl ma nesium halide with methyl-4,8,12-trimethyl tridecyl ketone and thereafter refluxing the resultant tertiary alcohol under acidic conditions to de-alkylate the ether linkages thereof and cyclize to the corresponding B-hydroxy tocopherol-like chroman.

5. The process of making alpha tocopherol which comprises reacting beta-(3,6-dialkoxy- 2,4,5-trimethyi phenyl) ethyl magnesium halide with methyl-4,8,l2-trimethyl tridecyl ketone and thereafter refluxing the resultant tertiary alcoho] under acidic condithl to de-alkylate the ether linkages and cycllle to alpha tocopherol.

6. The method of making tocopherol-like chroman compounds which comprises reacting a 3,6-

dialkoxy phenyl magnesium halide with ethylene Rs-CO-Re where one of the radicals in the structure RsCO-Re is alkyl and the other or said radicals is selected from the group consisting of hydrogen and alkyl, and refluxing the resultant tertiary alcohol under acidic conditions to de-alkylate the ether linkages of said tertiary alcohol and cyclize to the corresponding B-hydroxy chroman.

7. The method of making alpha tocopherol which comprises reacting 3,6-dialkoxy-2,4,5-trimethyl phenyl magnesium halide with ethylene oxide, acidifying and extracting the resultant beta hydroxy ethyl trimethyl hydroquinone diether, reacting said diether with a compound selected from. the class consisting of thionyl chloride and phosphorous tribromide, reacting the resultant compound with magnesium to IOIm the corresponding beta-i3,6-d1alkoxy-2,4,5-trimethy1 phenyi) ethyl magnesium halide, refluxing the latter with methyl-4,8,l2-trlmethyl tridecyl ketone to form the corresponding tertiary alcohol, and refluxing said tertiary alcohol under acidic conditions to de-alkylate the ether linkages thereof and cyclize to alpha tocopherol.

8. The method or making alpha tocopherol which comprises reacting 3,o-dialkoxy-2,4,5-trimethyl phenyl magnesium nahde with ethylene oxide, acidilyi and extracting the resultant beta hyaroxy etnyl trimetnyl hydroquinone diether, reacting said diether with tmonyl chloride in benzene, reacting the resultant compound with magnesium in the presence or a low-boning point alxyl nanoe to rolm me COIl'GSDOlICllUE beta-(3,6-a1alxoxy-23fl-uumetnyl pnenyl) ethyl magnesium chloride, renuxmg the latter with metnyl-4,a,l2-tnmetnyl trluecyl ketone to i'orm the corresponding tertiary alcohol, and refluxing said tertiary alcohol under acidic conditions to de-alkylate the ether linkages and cyclize to the desired alpha tocopherol.

9. The method or making alpha tocopherol which comprises reacting 3,o-dialkoxy-z,4,5-trimethyl phenyl magnesium halide with ethylene oxide, acidifying and extracting the resultant beta hydroxy ethyl trimethyl hydroquinone diether, reacting said diether with thionyl chloride in ethyl ether, reacting the resultant compound with magnesium in the presence of a low-boiling point alkyl halide to form the corresponding beta-(3,6-dialkoxy-2,4,5-trimethyl phenyl) ethyl magnesium chloride, refluxing the latter with methyl-4,8,12-trimethyl tridecyl ketone to form the corresponding tertiary alcohol, and refluxing said tertiary alcohol under acidic conditions to de-alkylate the ether linkages and cyclize to the desired alpha tocopherol.

10. The method of making alpha tocopherol which comprises reacting 3,6-dialkoxy-2,4,5-trimethyl phenyl magnesium halide with ethylene form the corresponding beta-(3,6-dialkoxy-2,4,5-

trimethyl phenyl) ethyl magnesium bromide, refluxing the latter with methyl-4,8,12-trimethyl 5 tocopheroi.

trideoyl ketone to form the corresponding tertiary'alcohol, and refluxing said tertiary alcohol under acidic conditions to de-alkylate the ether linkages thereof and cyclize to the desired alpha LEE IRVIN SMITH. HENRY C. MILLER. 

